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143 results on '"William A. Gahl"'

1. MYH2-associated myopathy caused by a novel splice-site variant

Author: Thomas A. Cassini, May Christine V. Malicdan, Ellen F. Macnamara, Tanya Lehky, Iren Horkayne-Szakaly, Yan Huang, Robert Jones, Rena Godfrey, Lynne Wolfe, William A Gahl, and Camilo Toro
Subjects: Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Published: 2023
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2. Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism

Author: Athena Cavounidis, Sumeet Pandey, Melania Capitani, Matthias Friedrich, Amy Cross, Lisa Gartner, Dominik Aschenbrenner, Seunghee Kim-Schulze, Ying Ka Lam, Georgina Berridge, Dermot P.B. McGovern, Benedikt Kessler, Roman Fischer, Paul Klenerman, Joanna Hester, Fadi Issa, Esther A. Torres, Fiona Powrie, Bernadette R. Gochuico, William A. Gahl, Louis Cohen, and Holm H. Uhlig
Subjects: Proteomics, Inflammation, Hermanski-Pudlak Syndrome, TOR Serine-Threonine Kinases, Immunology, Humans, Immunology and Allergy, Lipids
Abstract: Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1. We performed mass cytometry, proteomic and transcriptomic analyses to investigate peripheral blood cells and serum of HPS-1 patients. Using spatial transcriptomics, granuloma-associated signatures in the tissue of an HPS-1 patient with granulomatous colitis were dissected. In vitro studies were conducted to investigate anti-microbial responses of HPS-1 patient macrophages and cell lines. Monocytes of HPS-1 patients exhibit an inflammatory phenotype associated with dysregulated TNF, IL-1α, OSM in serum, and monocyte-derived macrophages. Inflammatory macrophages accumulate in the intestine and granuloma-associated macrophages in HPS-1 show transcriptional signatures suggestive of a lipid storage and metabolic defect. We show that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. Rab32-mediated mTOR signaling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation.
Published: 2022
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3. PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation

Author: Sangwoo T, Han, Andrew C, Kim, Karolyn, Garcia, Lisa A, Schimmenti, Ellen, Macnamara, Undiagnosed Diseases, Network, William A, Gahl, May C, Malicdan, and Cynthia J, Tifft
Subjects: Hypoxanthine Phosphoribosyltransferase, Lesch-Nyhan Syndrome, Autism Spectrum Disorder, Endocrinology, Diabetes and Metabolism, Proteins, Biochemistry, Article, Phenotype, Endocrinology, Protein Biosynthesis, Genetics, Humans, Intramolecular Transferases, Molecular Biology
Abstract: Protein translation is a highly regulated process involving the interaction of numerous genes on every component of the protein translation machinery. Upregulated protein translation is a hallmark of cancer and is implicated in autism spectrum disorder, but the risks of developing each disease do not appear to be correlated with one another. In this study we identified two siblings from the NIH Undiagnosed Diseases Program with loss of function variants in PUS7, a gene previously implicated in the regulation of total protein translation. These patients exhibited a neurodevelopmental phenotype including autism spectrum disorder in the proband. Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1. Patient fibroblasts demonstrated upregulation of protein synthesis, including elevated MYC protein, but did not exhibit increased rates of cell proliferation. Interestingly, the dysregulation of protein translation also resulted in mildly decreased levels of HPRT1 protein suggesting an association between dysregulated protein translation and the LNS-like phenotypic findings. These findings strengthen the correlation between neurodevelopmental disease, particularly autism spectrum disorders, and the rate of protein translation.
Published: 2022
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4. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Author: Thomas A. Ravenscroft, Jennifer B. Phillips, Elizabeth Fieg, Sameer S. Bajikar, Judy Peirce, Jeremy Wegner, Alia A. Luna, Eric J. Fox, Yi-Lin Yan, Jill A. Rosenfeld, Jonathan Zirin, Oguz Kanca, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanya, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, Paolo M. Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Paul J. Benke, Eric S. Cameron, Vincent Strehlow, Konrad Platzer, Rami Abou Jamra, Chiara Klöckner, Matthew Osmond, Thomas Licata, Samantha Rojas, David Dyment, Josephine S.C. Chong, Sharyn Lincoln, John H. Postlethwait, Joel Krier, and Hugo J. Bellen
Subjects: 0301 basic medicine, Craniofacial abnormality, Mutation, Missense, 030105 genetics & heredity, Biology, Article, Frameshift mutation, Craniofacial Abnormalities, 03 medical and health sciences, medicine, Animals, Humans, Missense mutation, Craniofacial, Allele, Zebrafish, Genetics (clinical), Loss function, Genetics, medicine.disease, biology.organism_classification, Phenotype, Spine, Growth Differentiation Factors, 030104 developmental biology, Bone Morphogenetic Proteins
Abstract: Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.
Published: 2021
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5. Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Author: Felix Marbach, Georgi Stoyanov, Florian Erger, Constantine A. Stratakis, Nikolaos Settas, Edra London, Jill A. Rosenfeld, Erin Torti, Chad Haldeman-Englert, Evgenia Sklirou, Elena Kessler, Sophia Ceulemans, Stanley F. Nelson, Julian A. Martinez-Agosto, Christina G.S. Palmer, Rebecca H. Signer, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Joel B. Krier, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Marisa V. Andrews, Dorothy K. Grange, Rebecca Willaert, Richard Person, Aida Telegrafi, Aaron Sievers, Magdalena Laugsch, Susanne Theiß, YuZhu Cheng, Olivier Lichtarge, Panagiotis Katsonis, Amber Stocco, and Christian P. Schaaf
Subjects: 0301 basic medicine, Apraxias, Autism Spectrum Disorder, Pain, Biology, Apraxia, Article, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Pregnancy, Intellectual Disability, Intellectual disability, medicine, Humans, Missense mutation, Global developmental delay, Genetics (clinical), Genetics, medicine.disease, Phenotype, Human genetics, 030104 developmental biology, Neurodevelopmental Disorders, Autism spectrum disorder, Cyclic AMP-Dependent Protein Kinase RIbeta Subunit, Female, 030217 neurology & neurosurgery
Abstract: Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
Published: 2021
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6. Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases

Author: Shilpa Nadimpalli Kobren, Dustin Baldridge, Matt Velinder, Joel B. Krier, Kimberly LeBlanc, Cecilia Esteves, Barbara N. Pusey, Stephan Züchner, Elizabeth Blue, Hane Lee, Alden Huang, Lisa Bastarache, Anna Bican, Joy Cogan, Shruti Marwaha, Anna Alkelai, David R. Murdock, Pengfei Liu, Daniel J. Wegner, Alexander J. Paul, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martinez-Agosto, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stanley F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca H. Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, and Shamil R. Sunyaev
Subjects: Prioritization, Genome, medicine.diagnostic_test, Genomic sequencing, Multimodal data, Computational Biology, Structural variant, Genomics, Undiagnosed Diseases, Data science, Shruti, Article, Workflow, Biomedical data, medicine, Humans, Genetic Testing, Psychology, Software, Genetics (clinical), Genetic testing
Abstract: Author(s): Kobren, Shilpa Nadimpalli; Baldridge, Dustin; Velinder, Matt; Krier, Joel B; LeBlanc, Kimberly; Esteves, Cecilia; Pusey, Barbara N; Zuchner, Stephan; Blue, Elizabeth; Lee, Hane; Huang, Alden; Bastarache, Lisa; Bican, Anna; Cogan, Joy; Marwaha, Shruti; Alkelai, Anna; Murdock, David R; Liu, Pengfei; Wegner, Daniel J; Paul, Alexander J; Undiagnosed Diseases Network; Sunyaev, Shamil R; Kohane, Isaac S | Abstract: PurposeGenomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.MethodsWe collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.ResultsWe found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.ConclusionThe largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.
Published: 2021
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7. A concurrent dual analysis of genomic data augments diagnoses: Experiences of 2 clinical sites in the Undiagnosed Diseases Network

Author: Rebecca C. Spillmann, Queenie K.-G. Tan, Chloe Reuter, Kelly Schoch, Jennefer Kohler, Devon Bonner, Diane Zastrow, Anna Alkelai, Evan Baugh, Heidi Cope, Shruti Marwaha, Matthew T. Wheeler, Jonathan A. Bernstein, Vandana Shashi, Maria T. Acosta, Margaret Adam, David R. Adams, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Hugo J. Bellen, Jimmy Bennet, Beverly Berg-Rood, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Thomas Cassini, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Madison P. Goldrich, Alana Grajewski, Irma Gutierrez, Don Hadley, Sihoun Hahn, Rizwan Hamid, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Wendy Introne, Rosario Isasi, Kosuke Izumi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Lefkothea Karaviti, Jennifer Kennedy, Shamika Ketkar, Dana Kiley, Gonench Kilich, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Kimberly LeBlanc, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Rachel Mahoney, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Jacob McCauley, Allyn McConkie-Rosell, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Mariko Nakano-Okuno, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Anna Raper, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Mario Saporta, Judy Schaechter, Timothy Schedl, C. Ron Scott, Daryl A. Scott, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz-Hubshman, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Jordan Whitlock, Lynne A. Wolfe, Kim Worley, Changrui Xiao, Shinya Yamamoto, John Yang, Diane B. Zastrow, Zhe Zhang, Chunli Zhao, and Stephan Zuchner
Subjects: Genetics (clinical)
Published: 2023
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8. One is the loneliest number: genotypic matchmaking using the electronic health record

Author: Nichole Hayes, Euan A. Ashley, Laura A. Mamounas, Allyn McConkie-Rosell, Shirley Sutton, John J.E. Mulvihill, John H. Postlethwait, Richard L. Maas, Jennefer N. Kohler, Dana Kiley, Joel B. Krier, Pankaj B. Agrawal, Xue Zhong Liu, Josh F. Peterson, Jill A. Rosenfeld, Thomas May, Jennifer E. Kyle, David A. Sweetser, Neil H. Parker, Jeanette C. Papp, Manish J. Butte, Calum A. MacRae, Rong Mao, Vandana Shashi, Christopher A. Walsh, Alica M. Goldman, Gabor T. Marth, Sharyn A. Lincoln, David Goldstein, Colleen E. McCormack, Byron L. Lam, Elly Brokamp, Lynette Rives, Lee-kai Wang, Lorraine Potocki, Mary Koziura, Matthew T. Wheeler, Teri A. Manolio, Camille L. Birch, Moretti Paolo, Willa Thorson, Fariha Jamal, Cynthia M. Cooper, Yong Huang, Matt Velinder, Catherine H. Sillari, Archana Raja, Andrea L. Gropman, J. Carl Pallais, Amy K. Robertson, Dave Viskochil, William J. Craigen, Thomas C. Markello, Devin Oglesbee, Olveen Carrasquillo, Precilla D'Souza, Lorenzo D. Botto, Hugo J. Bellen, Susan L. Samson, Jim Bale, Lisa Shakachite, Catherine Groden, Kathleen Shields, Jimann Shin, Carlos Ferreira, Lynne A. Wolfe, Melissa A. Haendel, Brent L. Fogel, Joan M. Stoler, Rebecca C. Spillmann, Roy C. Levitt, Gary D. Clark, Daniel J. Wegner, Gill Bejerano, Deborah Krakow, Ashok Balasubramanyam, J. Scott Newberry, Heidi Cope, Jijun Wan, Sandra K. Loo, Laura Duncan, Elizabeth A. Worthey, Leigh Anne Tang, Mercedes E. Alejandro, Matthew Might, Cecelia P. Tamburro, Patrick Allard, Joseph Loscalzo, Bret L. Bostwick, Lisa Emrick, Sarah K. Nicholas, David R. Murdock, Jeremy D. Woods, Alana L. Grajewski, Eva H. Baker, Lindsay C. Burrage, Stephen Pak, Camilo Toro, Ashley Andrews, James P. Orengo, Shawn Levy, Lance H. Rodan, Kelly Schoch, Jyoti G. Dayal, Thomas O. Metz, Kathy Sisco, Stephanie Bivona, Paolo Moretti, Braden E. Boone, Mahshid S. Azamian, Nicole M. Walley, Esteban C. Dell'Angelica, Rosario Isasi, Jacinda B. Sampson, F. Sessions Cole, Guoyun Yu, Rena A. Godfrey, John F. Bohnsack, Elizabeth A. Burke, John H. Newman, Alden Y. Huang, Patricia A. Ward, Barbara N. Pusey, Maria T. Acosta, Alan H. Beggs, Melissa A. Walker, Shweta U. Dhar, Edwin K. Silverman, Stephan Züchner, Ian R. Lanza, Bobbie-Jo M. Webb-Robertson, Anastasia L. Wise, Angela Jones, Nicholas Stong, Irman Forghani, Matthew H. Brush, Michael F. Wangler, Jonathan A. Bernstein, Aaron R. Quinlan, David D. Draper, Pinar Bayrak-Toydemir, Diane B. Zastrow, Daniel C. Dorset, Anna Bican, David J. Eckstein, Janet S. Sinsheimer, Isaac S. Kohane, Hsiao-Tuan Chao, May Christine V. Malicdan, C. Christopher Lau, Mariska Davids, Eva Morava-Kozicz, Beth A. Martin, Daryl A. Scott, Prashant Sharma, Elizabeth L. Fieg, Lauren C. Briere, Shinya Yamamoto, Devon Bonner, Ralph L. Sacco, Amanda J. Yoon, John Yang, Katrina M. Waters, Carlos A. Bacino, Pengfei Liu, Brendan Lee, Lisa Bastarache, Emily G. Kelley, Tiphanie P. Vogel, Jason Hom, Marta M. Majcherska, Robb Rowley, Liliana Fernandez, Carsten Bonnenmann, Stanley F. Nelson, Colleen E. Wahl, Guney Bademci, Justin Alvey, Naghmeh Dorrani, Hane Lee, Lefkothea P. Karaviti, Monte Westerfield, John A. Phillips, Laurel A. Cobban, Chunli Zhao, Nicola Longo, Donna M. Krasnewich, Ta Chen Peter Chang, Tiina K. Urv, Christine M. Eng, Chloe M. Reuter, Ingrid A. Holm, Jozef Lazar, Emilie D. Douine, Susan A. Korrick, Alexa T. McCray, Richard A. Lewis, Ronit Marom, Kimberly LeBlanc, Cynthia J. Tifft, Cecilia Esteves, David R. Adams, Donna M. Brown, Avi Nath, Rebecca Signer, Martin G. Martin, Julian A. Martinez-Agosto, Jacob L. McCauley, Alyssa A. Tran, Jennifer A. Sullivan, William A. Gahl, Brendan C. Lanpher, Marie Morimoto, Donna Novacic, Jean-Philippe F. Gourdine, Paul G. Fisher, Fred F. Telischi, Shruti Marwaha, Heather A. Colley, Queenie K.-G. Tan, Seema R. Lalani, Deborah Barbouth, Jennifer E. Posey, Yong-hui Jiang, Jennifer Wambach, Mario Saporta, Jean M. Johnston, Dustin Baldridge, Timothy Schedl, Pace Laura, Ellen Macnamara, Joy D. Cogan, Kevin S. Smith, David M. Koeller, Genecee Renteria, Maura R.Z. Ruzhnikov, Christina G.S. Palmer, Valerie Maduro, Frances A. High, Gerard T. Berry, Holly K. Tabor, Terra R. Coakley, Surendra Dasari, Neil A. Hanchard, David P. Bick, Laure Fresard, Rizwan Hamid, Lilianna Solnica-Krezel, Gabriel F. Batzli, Judy Schaechter, John C. Carey, Tyra Estwick, and Mustafa Tekin
Subjects: World Wide Web, Electronic health record, Biology, Genetics (clinical)
Published: 2021
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9. Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science

Author: Kelly Schoch, Cecilia Esteves, Anna Bican, Rebecca Spillmann, Heidi Cope, Allyn McConkie-Rosell, Nicole Walley, Liliana Fernandez, Jennefer N. Kohler, Devon Bonner, Chloe Reuter, Nicholas Stong, John J. Mulvihill, Donna Novacic, Lynne Wolfe, Ayat Abdelbaki, Camilo Toro, Cyndi Tifft, May Malicdan, William Gahl, Pengfei Liu, John Newman, David B. Goldstein, Jason Hom, Jacinda Sampson, Matthew T. Wheeler, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J.Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J.Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C.Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Terra R. Coakley, Paul G. Fisher, Laure Fresard, Yong Huang, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, and Joy Cogan
Subjects: Exome sequencing, 0301 basic medicine, Computational biology, 030105 genetics & heredity, Genome sequencing, Article, DNA sequencing, Retrospective data, 03 medical and health sciences, Rare Diseases, Animals, Humans, Genomic medicine, Medicine, Medical diagnosis, Exome, Genetics (clinical), Retrospective Studies, Disease gene, business.industry, Genomics, 030104 developmental biology, Phenotyping, New disease, Undiagnosed diseases, Ultra-rare diseases, business
Abstract: Purpose The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices. Methods We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods. Results Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling. Conclusion Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.
Published: 2021
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10. Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)

Author: Frank Rutsch, Mary E. Hackbarth, Mary Scott Roberts, Rachel I Gafni, Margaret Whelpley, Michael A. Levine, Kristen S. Pan, William A. Gahl, Ellen Macnamara, Christina Jacobsen, Ingrid A. Holm, Carlos Ferreira, Sisi Wang, Esra Dikoglu, Timothy E Corden, M Zulf Mughal, Iris R Hartley, Douglas R. Rosing, Joy Bryant, Emily Y. Chew, Kerstin Müller, Marcus Y. Chen, and Shira G. Ziegler
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, ENPP1 Deficiency, Autosomal Recessive Hypophosphatemic Rickets type 2, Hearing loss, ABCC6, Rickets, 030105 genetics & heredity, Article, Generalized arterial calcification, Generalized Arterial Calcification of Infancy, 03 medical and health sciences, medicine, Pseudoxanthoma Elasticum, Genetics (clinical), biology, business.industry, Incidence (epidemiology), Pseudoxanthoma elasticum, medicine.disease, Hypophosphatemic Rickets, 030104 developmental biology, biology.protein, ABCC6 Deficiency, medicine.symptom, business, Calcification
Abstract: Purpose Generalized Arterial Calcification of Infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods We performed deep phenotyping of 20 GACI survivors. Results Sixteen of twenty subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusions GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
Published: 2021
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11. Biallelic variants in two complex I genes cause abnormal splicing defects in probands with mild Leigh syndrome

Author: Camilo Toro, Yan Huang, Brandon R. Barton, Thomas Johnstone, Jennifer Wang, May Christine V. Malicdan, William A. Gahl, Rena A. Godfrey, Daron L. Ross, Catherine Groden, and Nicholas Balanda
Subjects: Adult, Male, 0301 basic medicine, Proband, Adolescent, RNA Splicing, Endocrinology, Diabetes and Metabolism, Mutant, Oxidative phosphorylation, 030105 genetics & heredity, Biology, Biochemistry, Article, Mitochondrial Proteins, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Genetics, Humans, Genetic Predisposition to Disease, Decompensation, Child, Molecular Biology, Gene, Alleles, Electron Transport Complex I, Genetic heterogeneity, NADH Dehydrogenase, Phenotype, Molecular biology, Mitochondria, Pedigree, Mutation, RNA splicing, Female, Leigh Disease, 030217 neurology & neurosurgery
Abstract: Leigh syndrome is a genetically heterogeneous disorder resulting from deficient oxidative energy biogenesis. The syndrome is characterized by subacute episodic decompensations, transiently elevated lactate, and necrotizing brain lesions most often in the striatum and brainstem. Acute decompensation is often triggered by viral infections. Sequalae from repeated episodes leads to progressive neurological deterioration and death. The severity of Leigh syndrome varies widely, from a rapid demise in childhood to rare adult presentations. Although the causes of Leigh syndrome include genes affecting a variety of different pathways, more than 75 of them are nuclear or mitochondrial encoded genes involved in the assembly and catalytic activity of mitochondrial respiratory complex I. Here we report the detailed clinical and molecular phenotype of two adults with mild presentations of NDUFS3 and NDUFAF6-related Leigh Syndrome. Mitochondrial assays revealed slightly reduced complex I activity in one proband and normal complex I activity in the other. The proband with NDUFS3-related Leigh syndrome was mildly affected and lived into adulthood with novel biallelic variants causing aberrant mRNA splicing (NM_004551.2:c.419G > A; p.Arg140Gln; NM_004551.2:c.381 + 6 T > C). The proband with NDUFAF6-related Leigh syndrome had biallelic variants that cause defects in mRNA splicing (NM_152416.3:c.371 T > C; p.Ile124Thr; NM_152416.3:c.420 + 2_420 + 3insTA). The mild phenotypes of these two individuals may be attributed to some residual production of normal NDUFS3 and NDUFAF6 proteins by NDUFS3 and NDUFAF6 mRNA isoforms alongside mutant transcripts. Taken together, these cases reported herein suggest that splice-regulatory variants to complex I proteins could result in milder phenotypes.
Published: 2020
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12. Prospective evaluation of kidney and liver disease in autosomal recessive polycystic kidney disease-congenital hepatic fibrosis

Author: Meral Gunay-Aygun, Nehna Abdul Majeed, Linda Lukose, Theo Heller, Joy Bryant, Esperanza Font-Montgomery, Peter L. Choyke, Peter Veppumthara, Ismail B. Turkbey, and William A. Gahl
Subjects: Adult, Liver Cirrhosis, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Receptors, Cell Surface, 030105 genetics & heredity, Liver transplantation, Kidney, Compound heterozygosity, Biochemistry, Gastroenterology, Article, Cohort Studies, Young Adult, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Endocrinology, Internal medicine, Hypertension, Portal, Genetics, medicine, Humans, Prospective Studies, Child, Molecular Biology, Kidney transplantation, Polycystic Kidney, Autosomal Recessive, business.industry, Genetic Diseases, Inborn, medicine.disease, Kidney Transplantation, Autosomal Recessive Polycystic Kidney Disease, Liver Transplantation, Cross-Sectional Studies, medicine.anatomical_structure, Liver, Disease Progression, Portal hypertension, Congenital hepatic fibrosis, Female, business, 030217 neurology & neurosurgery
Abstract: Background and objectives We have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
Published: 2020
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13. Aortic distensibility in alkaptonuria

Author: Wendy J. Introne, Kevin J. O'Brien, Jeannie H. Yu, Marcus Y. Chen, Sujata M Shanbhag, Rashmi Thimmapuram, W. Patricia Bandettini, and William A. Gahl
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Cardiovascular health, Aorta, Thoracic, 030105 genetics & heredity, Alkaptonuria, Biochemistry, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, medicine.artery, Hyperlipidemia, Genetics, medicine, Humans, Thoracic aorta, Homogentisic acid, Vascular Calcification, Molecular Biology, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Middle Aged, Prognosis, medicine.disease, chemistry, Case-Control Studies, Coronary artery calcification, cardiovascular system, Cardiology, Female, Aortic stiffness, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Introduction Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism resulting in an accumulation of homogentisic acid oxidation products in the joints and cardiovascular system. Aortic distensibility may be a non-invasive indicator of cardiovascular complications. Descending thoracic aortic distensibility in alkaptonuria has not been studied. Methods Patients diagnosed with alkaptonuria underwent Magnetic Resonance Imaging (MRI) and gated non-contrast and contrast-enhanced cardiovascular computed tomography. Using MRI cine images, aortic distensibility of the descending thoracic aorta was determined. Results Seventy-six patients with alkaptonuria were imaged. When compared to literature normal values, aortic distensibility in AKU was impaired (5.2 vs 6.2 × 10−3, p Conclusions Patients with alkaptonuria have impaired aortic distensibility, which is likely an early marker for reduced cardiovascular health. Variables such as age, hypertension, hyperlipidemia, and aortic and coronary calcification were associated with impaired distensibility.
Published: 2020
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14. De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

Author: Dongxue Mao, Chloe M. Reuter, Maura R.Z. Ruzhnikov, Anita E. Beck, Emily G. Farrow, Lisa T. Emrick, Jill A. Rosenfeld, Katherine M. Mackenzie, Laurie Robak, Matthew T. Wheeler, Lindsay C. Burrage, Mahim Jain, Pengfei Liu, Daniel Calame, Sébastien Küry, Martin Sillesen, Klaus Schmitz-Abe, Davide Tonduti, Luigina Spaccini, Maria Iascone, Casie A. Genetti, Mary K. Koenig, Madeline Graf, Alyssa Tran, Mercedes Alejandro, Brendan H. Lee, Isabelle Thiffault, Pankaj B. Agrawal, Jonathan A. Bernstein, Hugo J. Bellen, Hsiao-Tuan Chao, Maria T. Acosta, Margaret Adam, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Raphael Bernier, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Elizabeth A. Burke, Manish J. Butte, Peter Byers, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Yong-hui Jiang, Jean M. Johnston, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Kimberly LeBlanc, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Genecee Renteria, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Proband, Ataxia, Adolescent, Developmental Disabilities, Nervous System Malformations, Leukoencephalopathy, eIF-2 Kinase, 03 medical and health sciences, 0302 clinical medicine, Leukoencephalopathies, Report, Genetics, medicine, Humans, Missense mutation, Kinase activity, Child, Genetics (clinical), biology, Leukodystrophy, Genetic Variation, Infant, medicine.disease, White Matter, Hypotonia, Hereditary Central Nervous System Demyelinating Diseases, 030104 developmental biology, Child, Preschool, eIF2B, Immunology, biology.protein, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract: EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
Published: 2020
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15. A concerted action to explore therapies for free sialic acid storage disease

Author: Marjan Huizing, Steven U. Walkley, Melissa Wasserstein, Christine Anne-Longin, Raymond Y. Wang, Richard Reimer, Laura Pollard, Liisa Paavola, May Christine Malicdan, Marya S. Sabir, Petcharat Leoyklang, David R. Adams, and William A. Gahl
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Molecular Biology, Biochemistry
Published: 2023
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16. Position paper of the undiagnosed diseases network international with respect to the establishment of the journal Rare-Open research in rare diseases

Author: William A. Gahl, Olaf Bodamer, Helene Cederroth, Roberto Giugliani, Eric Klee, Manuel Posada De La Paz, Olaf Horst Riess, and Domenica Taruscio
Published: 2023
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17. A concerted action to explore therapies for free sialic acid storage disease (FSASD)

Author: Marjan Huizing, Marya S. Sabir, Mary E. Hackbarth, Lynne A. Wolfe, Melissa P. Wasserstein, David R. Adams, May C. Malicdan, William A. Gahl, Steven U. Walkley, and F.S.A.S.D. Consortium
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Molecular Biology, Biochemistry
Published: 2022
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18. Magnetic Resonance Imaging characteristics in case of TOR1AIP1 muscular dystrophy

Author: Aashim Bhatia, Bret C. Mobley, Joy Cogan, Mary E. Koziura, Elly Brokamp, John Phillips, John Newman, Steven A. Moore, Rizwan Hamid, Maria T. Acosta, David R. Adams, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Sandra K. Loo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: medicine.medical_specialty, Adolescent, Gene mutation, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Muscular dystrophy, Muscle, Skeletal, Gluteal muscles, Muscle Weakness, Muscle biopsy, medicine.diagnostic_test, business.industry, Muscle weakness, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Muscular Atrophy, medicine.anatomical_structure, Lower Extremity, Muscular Dystrophies, Limb-Girdle, 030220 oncology & carcinogenesis, Female, Radiology, Iliopsoas, medicine.symptom, business, Molecular Chaperones
Abstract: Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.
Published: 2019
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19. Cerebral and portal vein thrombosis, macrocephaly and atypical absence seizures in Glycosylphosphatidyl inositol deficiency due to a PIGM promoter mutation

Author: Carlos Ferreira, Amit Mary Philosoph, Assaf Arie Barg, Dror S. Shouval, Helly Vernitsky, Ben Pode-Shakked, Gali Heimer, Dana Levinkopf, Gili Kenet, William A. Gahl, Yair Anikster, Mariska Davids, Dina Marek-Yagel, Thierry Vilboux, Ninette Amariglio, Avishay Lahad, Marina Safaniev, Michalle Soudack, Chen Hoffmann, Maya Lodzki, Bruria Ben-Zeev, May Christine V. Malicdan, Naomi Pode-Shakked, Alvit Veber, Ayman Daka, and Batia Weiss
Subjects: Male, 0301 basic medicine, Adolescent, Glycosylphosphatidylinositols, Endocrinology, Diabetes and Metabolism, Atypical absence seizures, Prenatal diagnosis, Disease, 030105 genetics & heredity, medicine.disease_cause, Bioinformatics, Mannosyltransferases, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Seizures, Genetics, medicine, Humans, Child, Promoter Regions, Genetic, Molecular Biology, Mutation, Portal Vein, business.industry, Macrocephaly, Infant, Thrombosis, Sodium phenylbutyrate, medicine.disease, Magnetic Resonance Imaging, Phenotype, Megalencephaly, Portal vein thrombosis, Child, Preschool, Female, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Defects of the glycosylphosphatidylinositol (GPI) biosynthesis pathway constitute an emerging subgroup of congenital disorders of glycosylation with heterogeneous phenotypes. A mutation in the promoter of PIGM, resulting in a syndrome with portal vein thrombosis and persistent absence seizures, was previously described in three patients. We now report four additional patients in two unrelated families, with further clinical, biochemical and molecular delineation of this unique entity. We also describe the first prenatal diagnosis of PIGM deficiency, allowing characterization of the natural history of the disease from birth. The patients described herein expand the phenotypic spectrum of PIGM deficiency to include macrocephaly and infantile-onset cerebrovascular thrombotic events. Finally, we offer insights regarding targeted treatment of this rare disorder with sodium phenylbutyrate.
Published: 2019
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20. Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification

Author: Elena-Raluca Nicoli, Mary R. Weston, Mary Hackbarth, Alissa Becerril, Austin Larson, Wadih M. Zein, Peter R. Baker, John Douglas Burke, Heidi Dorward, Mariska Davids, Yan Huang, David R. Adams, Patricia M. Zerfas, Dong Chen, Thomas C. Markello, Camilo Toro, Tim Wood, Gene Elliott, Mylinh Vu, Wei Zheng, Lisa J. Garrett, Cynthia J. Tifft, William A. Gahl, Debra L. Day-Salvatore, Joseph A. Mindell, May Christine V. Malicdan, Maria T. Acosta, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Albinism, Antiporter, Vacuole, Article, Organomegaly, Mice, Xenopus laevis, 03 medical and health sciences, 0302 clinical medicine, Chloride Channels, Lysosome, Genetics, medicine, Lysosomal storage disease, Animals, Humans, Genetics (clinical), Hypopigmentation, biology, Chemistry, Genetic Variation, Infant, Fibroblasts, Hydrogen-Ion Concentration, medicine.disease, Molecular biology, Lysosomal Storage Diseases, 030104 developmental biology, medicine.anatomical_structure, Oocytes, biology.protein, Female, CLCN7, medicine.symptom, Lysosomes, Acids, 030217 neurology & neurosurgery, Intracellular
Abstract: Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl(−)/H(+) exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.
Published: 2019
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21. Glycomics in rare diseases: from diagnosis tomechanism

Author: Mohd A. Raihan, Mariska Davids, May Christine V. Malicdan, William A. Gahl, Miao He, David H. Adams, Lynne A. Wolfe, Megan S. Kane, Camilo Toro, Xueli Li, Cynthia J. Tifft, and Cornelius F. Boerkoel
Subjects: 0301 basic medicine, Protein glycosylation, Glycan, Glycosylation, Disease, Bioinformatics, Glycomics, 03 medical and health sciences, chemistry.chemical_compound, Rare Diseases, 0302 clinical medicine, Physiology (medical), Humans, Medicine, Exome sequencing, biology, business.industry, Biochemistry (medical), Public Health, Environmental and Occupational Health, General Medicine, Glycome, Phenotype, carbohydrates (lipids), 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, biology.protein, business
Abstract: The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) studies rare genetic disorders not only to achieve diagnoses, but to understand human biology. To ascertain the contribution of protein glycosylation to rare diseases, the NIH UDP used mass spectrometry to agnostically identify abnormalities of N-linked and O-linked glycans in plasma and free oligosaccharides in the urine of 207 patients. 60% of UDP patients had a glycome profile that deviated from control values in at least 1 fluid. Additional evaluation of the fibroblast glycome in 66 patients with abnormalities in plasma and/or urine revealed a consistent glycome phenotype in 83% of these cases. Many of these patients may have secondary glycosylation defects, since it is unlikely that they all have congenital disorders of glycosylation (CDGs). In fact, whole exome sequencing revealed only a few patients with CDGs, along with several others having disorders indirectly altering glycosylation. In summary, we describe a biochemical phenotyping screen to identify defects in protein glycosylation that can elucidate mechanisms of disease among NIH UDP patients.
Published: 2019
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22. Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients

Author: Prashant Sharma, William A. Gahl, Babak Behnam, Cynthia J. Tifft, Camille Wang, May Christine V. Malicdan, Mariska Davids, Camilo Toro, Wadih M. Zein, William Brian Gallantine, David R. Adams, Xenia Chepa-Lotrea, and Joseph J. Chin
Subjects: Adult, Male, 0301 basic medicine, Proband, Pathology, medicine.medical_specialty, Batten disease, Adolescent, Endocrinology, Diabetes and Metabolism, Vision Disorders, 030105 genetics & heredity, Biochemistry, Lipofuscin, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Neuronal Ceroid-Lipofuscinoses, Genetics, medicine, Humans, Exome, Child, Molecular Biology, Exome sequencing, business.industry, Endoplasmic reticulum, High-Throughput Nucleotide Sequencing, Membrane Proteins, Fibroblasts, medicine.disease, Phenotype, United States, Transmembrane protein, Pedigree, National Institutes of Health (U.S.), Mutation, Female, Neuronal ceroid lipofuscinosis, business, 030217 neurology & neurosurgery
Abstract: CLN6 is a transmembrane protein located in the endoplasmic reticulum that is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis (LINCL), and teenage and adult onset NCL without visual impairment. Here we describe two pediatric patients with LINCL from unrelated families who were evaluated at the National Institutes of Health. Both children exhibited typical phenotypes associated with LINCL except that they lacked the expected visual impairment. Whole exome sequencing identified novel biallelic mutations in CLN6, i.e., c.218-220dupGGT (p.Trp73dup) and c.296A > G (p.Lys99Arg) in Proband 1 and homozygous c.723G > T (p.Met241Ile) in Proband 2. Expression analysis in dermal fibroblasts showed a small increase in CLN6 protein levels. Electron micrographs of these fibroblasts demonstrated large numbers of small membrane-bound vesicles, in addition to lipofuscin deposits. LysoTracker™ Red intensity was increased in fibroblasts from both patients. This study supports a role for CLN6 in lysosomal homeostasis, and highlights the importance of considering CLN6 mutations in the diagnosis of Batten Disease even in patients with normal vision.
Published: 2019
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23. Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

Author: Keren Machol, Justine Rousseau, Sophie Ehresmann, Thomas Garcia, Thi Tuyet Mai Nguyen, Rebecca C. Spillmann, Jennifer A. Sullivan, Vandana Shashi, Yong-hui Jiang, Nicholas Stong, Elise Fiala, Marcia Willing, Rolph Pfundt, Tjitske Kleefstra, Megan T. Cho, Heather McLaughlin, Monica Rosello Piera, Carmen Orellana, Francisco Martínez, Alfonso Caro-Llopis, Sandra Monfort, Tony Roscioli, Cheng Yee Nixon, Michael F. Buckley, Anne Turner, Wendy D. Jones, Peter M. van Hasselt, Floris C. Hofstede, Koen L.I. van Gassen, Alice S. Brooks, Marjon A. van Slegtenhorst, Katherine Lachlan, Jessica Sebastian, Suneeta Madan-Khetarpal, Desai Sonal, Naidu Sakkubai, Julien Thevenon, Laurence Faivre, Alice Maurel, Slavé Petrovski, Ian D. Krantz, Jennifer M. Tarpinian, Jill A. Rosenfeld, Brendan H. Lee, Philippe M. Campeau, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Ani Dillon, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Carlos Ferreira, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew R. Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Jean M. Johnston, Angela L. Jones, Isaac S. Kohane, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Allen Lipson, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Matthew Might, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Kimberly Splinter, Joan M. Stoler, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer M. Valivullah, Eric Vilain, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Patricia A. Ward, Katrina M. Waters, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Diane B. Zastrow, Allison Zheng, and Clinical Genetics
Subjects: Male, 0301 basic medicine, Hypertrichosis, speech delay, Bafopathy, Developmental Disabilities, CACNB4, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Bafopathy, developmental delay, dysmorphisms, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorder, speech delay, transcriptome, Genetics(clinical), Child, Genetics (clinical), Genetics, Syndrome, Hypotonia, DNA-Binding Proteins, developmental delay, Corticogenesis, intellectual disability, Child, Preschool, Speech delay, Female, medicine.symptom, Hand Deformities, Congenital, dysmorphisms, Adolescent, Micrognathism, genotype-phenotype correlation, Biology, Chromatin remodeling, 03 medical and health sciences, Journal Article, medicine, Humans, Abnormalities, Multiple, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.disease, neurodevelopmental disorder, Reelin Protein, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Face, Mutation, biology.protein, transcriptome, Neck, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Contains fulltext : 202800.pdf (Publisher’s version ) (Open Access) SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
Published: 2019
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24. In memoriam: Jerry Allan Schneider, 1937–2021

Author: Bruce A, Barshop, Adam J, Jonas, William A, Gahl, and Jess G, Thoene
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Molecular Biology, Biochemistry
Published: 2022
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25. GENE VARIANTS ASSOCIATED WITH THROMBOCYTOPENIA WITH OR WITHOUT GNE MYOPATHY

Author: Jessica M. Jang, Marjan Huizing, Andrea Bowling, Caitlin Yuan, Nuria Carrillo, William A. Gahl, and Francis Rossignol
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Molecular Biology, Biochemistry
Published: 2022
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26. A novel experimental mouse model to investigate a free sialic acid storage disorder (Salla disease)

Author: Marya S. Sabir, Mary E. Hackbarth, John D. Burke, Lisa J. Garrett, Gene Elliott, Cecilia Rivas, Danielle A. Springer, Petcharat Leoyklang, Tannia S. Clark, Marjan Huizing, William A. Gahl, and May Christine V. Malicdan
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Molecular Biology, Biochemistry
Published: 2022
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27. Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism

Author: Katta M. Girisha, Cecilia Rivas, Laila Mahmoud, Hessa S. Alsaif, Abdel G. Elkahloun, Michaela Prochazkova, Georgia Ramantani, Steven P. Bodine, Dilek Colak, Matthew R. Herzog, John Douglas Burke, Joshi Stephen, Sheela Nampoothiri, Anju Shukla, William A. Gahl, Ascia Eskin, H. Douglas Morris, Tadafumi Yokoyama, Lisa Garrett, Salma M. Wakil, PV Suresh, Nathanial J. Tolman, Fowzan S. Alkuraya, Tawfeg Ben-Omran, Katharina Steindl, Siddaramappa J. Patil, Ashok B. Kulkarni, Rehab Ali, Julian A. Martinez-Agosto, May Christine V. Malicdan, Anita Rauch, Hane Lee, Pascal Joset, Patricia M. Zerfas, Stanley F. Nelson, Allison Zheng, Nicholas Balanda, and Sateesh Maddirevula
Subjects: Heart Defects, Congenital, Male, 0301 basic medicine, Hypertrichosis, Adolescent, Microarray, Developmental Disabilities, Biology, Nervous System Malformations, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Genetics, medicine, Animals, Humans, Abnormalities, Multiple, Global developmental delay, Hypertelorism, Craniofacial, Allele, Child, Alleles, Genetics (clinical), Mice, Knockout, Facies, Infant, Nuclear Proteins, medicine.disease, Phenotype, Mice, Inbred C57BL, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Female, medicine.symptom, Transcriptome, 030217 neurology & neurosurgery
Abstract: Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.
Published: 2018
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28. A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation

Author: Gen Nishimura, Tito Onyekweli, David A. Parry, Bernardo Blanco-Sánchez, Dawn L. Earl, Ganka Douglas, Clare V. Logan, Carlos Ferreira, Bobby G. Ng, Jeremy Wegner, Marte Gjøl Haug, Zöe Powis, Benjamin D. Solomon, Megan T. Cho, Ellen Macnamara, Lynne A. Wolfe, Ann Nordgren, Anna Hammarsjö, Melissa Gabriel, Zhi-Jie Xia, Angela L. Duker, Fulya Taylan, Kelly Radtke, Mariya Kozenko, Daniel R. Carvalho, Prashant Sharma, Hudson H. Freeze, Monte Westerfield, Kazuhiro Aoki, Michael B. Bober, Luis Rohena, Alvaro H Serrano Russi, Jennifer B. Phillips, Coleman T. Turgeon, Aurélie Clément, Giedre Grigelioniene, Tara E. Weixel, John A. Phillips, Rizwan Hamid, May Christine V. Malicdan, David H. Adams, George E. Tiller, Mariska Davids, Cynthia J. Tifft, Kimiyo Raymond, Andrew P. Jackson, Emma Tham, Hanne B Hove, Lauren Brick, Jakob Ek, Heiko Bratke, William G. Wilson, Michael Tiemeyer, and William A. Gahl
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Glycosylation, Decorin, Vesicular Transport Proteins, Golgi Apparatus, 030105 genetics & heredity, Endoplasmic Reticulum, Cell Line, Animals, Genetically Modified, Extracellular matrix, 03 medical and health sciences, symbols.namesake, chemistry.chemical_compound, Genetics, medicine, Animals, Humans, Child, Zebrafish, Genetics (clinical), biology, Infant, Heterozygote advantage, Fibroblasts, Golgi apparatus, medicine.disease, Molecular biology, Extracellular Matrix, Vesicular transport protein, Protein Transport, 030104 developmental biology, Amino Acid Substitution, Proteoglycan, chemistry, Child, Preschool, Fragile X Syndrome, biology.protein, symbols, Female, Proteoglycans, Primordial dwarfism
Abstract: The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.
Published: 2018
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29. Prolonged treatment with open-label pirfenidone in Hermansky-Pudlak syndrome pulmonary fibrosis

Author: Bernadette R. Gochuico, Melissa McGowan, Orhan Akal, Wendy J. Introne, Adrian Barbu, Kevin J. O'Brien, Samuel L. Seward, Melissa A. Merideth, Tulay Akal, and William A. Gahl
Subjects: Adult, Male, medicine.medical_specialty, Pyridones, Pulmonary Fibrosis, Endocrinology, Diabetes and Metabolism, Placebo, Single Center, Biochemistry, Gastroenterology, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Endocrinology, DLCO, Internal medicine, Pulmonary fibrosis, Genetics, medicine, Humans, 030212 general & internal medicine, Colitis, Adverse effect, Lung, Molecular Biology, Aged, business.industry, Pirfenidone, Middle Aged, respiratory system, medicine.disease, 030228 respiratory system, Hermanski-Pudlak Syndrome, Female, Tomography, X-Ray Computed, business, medicine.drug
Abstract: Purpose Limited information is available regarding chronic treatment with pirfenidone, an anti-fibrotic drug. Effects of long-term open-label pirfenidone were evaluated in a small cohort with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder with highly penetrant pulmonary fibrosis. Results Three patients with HPS pulmonary fibrosis treated with open-label pirfenidone and twenty-one historical controls randomized to placebo were studied at a single center. Mean duration of treatment with pirfenidone for 3 patients with HPS pulmonary fibrosis was 13.1 years. Annual changes in FVC and DLCO with pirfenidone treatment were 0.46 and − 0.93% predicted, respectively. In comparison, historical controls randomized to receive placebo experienced mean annual changes in FVC and DLCO of −4.4 and − 2.3% predicted, respectively. High-resolution computed tomography (HRCT) scans revealed improved ground glass opacities with development of minimal interstitial reticulations in 1 patient after 12.8 years of treatment with pirfenidone. Slowly progressive increase in bilateral interstitial fibrosis developed in a different patient, who received pirfenidone for 18.1 years and died at 73 years of age due to HPS pulmonary fibrosis. Another patient treated with pirfenidone for 8.4 years had attenuated ground glass opacification on HRCT scan and improved oxygenation; this patient died due to chronic complications from colitis, and not pulmonary fibrosis. Adverse effects were generally limited to mild gastrointestinal discomfort and transient elevations of alanine aminotransferase in one patient. Conclusions Chronic treatment with pirfenidone may provide clinical benefit with few adverse effects for some patients with HPS pulmonary fibrosis. These results suggest that compassionate use of pirfenidone could be considered on a case-by-case basis for patients with HPS pulmonary fibrosis.
Published: 2018
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30. Alström syndrome: Renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center

Author: Baris Turkbey, William A. Gahl, Joy Bryant, Juergen K Naggert, Daniela P Reyes-Capo, Peter L. Choyke, Meral Gunay-Aygun, Joan C. Han, Kathryn A. Carson, Meryl Waldman, and Jan D. Marshall
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Cardiomyopathy, Cell Cycle Proteins, Kidney, Biochemistry, Gastroenterology, Article, 03 medical and health sciences, Endocrinology, Insulin resistance, Internal medicine, Genetics, medicine, Humans, Obesity, Molecular Biology, Alstrom Syndrome, Dyslipidemias, business.industry, Retinal Degeneration, Proteins, Type 2 Diabetes Mellitus, medicine.disease, Ciliopathy, 030104 developmental biology, Mutation, Female, Kidney Diseases, Insulin Resistance, Metabolic syndrome, Cardiomyopathies, business, Dyslipidemia, Alström syndrome, Kidney disease
Abstract: Alström Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive liver and kidney disease, and normal cognitive function. ALMS1, the protein defective in this disorder, localizes to the cytoskeleton, microtubule organizing center, as well as the centrosomes and ciliary basal bodies and plays roles in formation and maintenance of cilia, cell cycle regulation, and endosomal trafficking. Kidney disease in this disorder has not been well characterized. We performed comprehensive multisystem evaluations on 38 patients. Kidney function decreased progressively; eGFR varied inversely with age (p = 0.002). Eighteen percent met the definition for chronic kidney disease (eGFR < 60 mL/min/1.73 m(2) and proteinuria); all were adults with median age of 32.8 (20.6–37.9) years. After adjusting for age, there were no significant associations of kidney dysfunction with type 2 diabetes mellitus, dyslipidemia, hypertension, cardiomyopathy or portal hypertension suggesting that kidney disease in AS is a primary manifestation of the syndrome due to lack of ALMS1 protein. Approximately one-third of patients had hyperechogenicity of the renal parenchyma on imaging. While strict control of type 2 diabetes mellitus may decrease kidney-related morbidity and mortality in Alström syndrome, identification of novel targeted therapies is needed.
Published: 2018
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31. De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome

Author: Casie A. Genetti, Sarah Hope Lincoln, William A. Gahl, Kiran Maski, Sahil Tembulkar, Eugene J. D'Angelo, Jiahai Shi, Alan H. Beggs, Robin J. Kleiman, Pankaj B. Agrawal, Catherine M. Biggs, Kathleen J. Sweadner, Niklas Smedemark-Margulies, Chrystal F. Mavros, Edward Yang, Gerard T. Berry, Alcy Torres, Devon Carroll, Kevin X. Liu, Kelsey Graber, Joseph Gonzalez-Heydrich, Catherine A. Brownstein, Kathryn J. Swoboda, and Fatma Dedeoglu
Subjects: 0301 basic medicine, lcsh:R5-920, Mutation, business.industry, Alternating hemiplegia of childhood, Compound heterozygosity, medicine.disease_cause, medicine.disease, 03 medical and health sciences, Muckle–Wells syndrome, 030104 developmental biology, Endocrinology, lcsh:Biology (General), Autism spectrum disorder, ATP1A3, Immunology, Genetics, Medicine, Spectrum disorder, lcsh:Medicine (General), business, lcsh:QH301-705.5, Molecular Biology, Exome sequencing
Abstract: Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5 years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype. Keywords: Autism spectrum disorder, Fatigue, Sleep disorder
Published: 2018
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32. Urine oligosaccharide screening by MALDI-TOF for the identification of NGLY1 deficiency

Author: Patricia L. Hall, Kimiyo Raymond, William A. Gahl, Carlos Ferreira, Lynne A. Wolfe, Hudson H. Freeze, Christina Lam, Gerard T. Berry, Kim K. Nickander, John J. Alexander, Caroline M. Watson, Jon D. Sharer, and Ghazia Asif
Subjects: Male, 0301 basic medicine, Analyte, Adolescent, Aspartylglucosaminuria, Endocrinology, Diabetes and Metabolism, Population, Oligosaccharides, Urine, Tandem mass spectrometry, Biochemistry, Young Adult, 03 medical and health sciences, Congenital Disorders of Glycosylation, Endocrinology, Tandem Mass Spectrometry, Genetics, medicine, Humans, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, Child, education, NGLY1, Molecular Biology, Exome, chemistry.chemical_classification, education.field_of_study, business.industry, Infant, Oligosaccharide, medicine.disease, 030104 developmental biology, chemistry, Child, Preschool, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Immunology, Female, business, Biomarkers
Abstract: N-glycanase deficiency (NGLY1 deficiency, NGLY1-CDDG), the first autosomal recessive congenital disorder of N-linked deglycosylation (CDDG), is caused by pathogenic variants in NGLY1. The majority of affected individuals have been identified using exome or genome sequencing. To date, no reliable, clinically available biomarkers have been identified. Urine oligosaccharide analysis was included as part of a routine evaluation for possible biomarkers in patients with confirmed NGLY1-CDDG. During the qualitative review of oligosaccharide profiles by an experienced laboratory director an abnormal analyte with a proposed structure of Neu5Ac1Hex1GlcNAc1-Asn was identified in NGLY1-CDDG patient urine samples. The same species has been observed in profiles from individuals affected with aspartylglucosaminuria, although the complete spectra are not identical. Additional studies using tandem mass spectrometry confirmed the analyte's structure. In addition to the known NGLY1-CDDG patients identified by this analysis, a single case was identified in a population referred for clinical testing who subsequently had a diagnosis of NGLY1-CDDG confirmed by molecular testing. Urine oligosaccharide screening by MALDI-TOF MS can identify individuals with NGLY1-CDDG. In addition, this potential biomarker might also be used to monitor the effectiveness of therapeutic options as they become available.
Published: 2018
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33. Correction: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author: Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, and Ping Yee Billie Au
Subjects: Genetics (clinical)
Published: 2021
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34. Safety, pharmacokinetics and sialic acid production after oral administration of N -acetylmannosamine (ManNAc) to subjects with GNE myopathy

Author: Carla Ciccone, Nuria Carrillo, Barry R. Goldspiel, John C. McKew, Nora Yang, May Christine V. Malicdan, Amy Wang, Frank Celeste, Lea Latham, Pramod S. Terse, James Cradock, Marjan Huizing, Xin Xu, William A. Gahl, and Selwyn Yorke
Subjects: Adult, Male, 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Administration, Oral, Biology, Pharmacology, Biochemistry, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Atrophy, Double-Blind Method, Pharmacokinetics, Oral administration, N-Acetylmannosamine, Genetics, medicine, Animals, Humans, Myopathy, Molecular Biology, Alleles, Aged, Dose-Response Relationship, Drug, Muscles, Homozygote, Muscle weakness, Hexosamines, Middle Aged, medicine.disease, N-Acetylneuraminic Acid, Sialic acid, Distal Myopathies, Phosphotransferases (Alcohol Group Acceptor), 030104 developmental biology, chemistry, Mutation, Female, medicine.symptom, N-Acetylneuraminic acid, 030217 neurology & neurosurgery
Abstract: GNE myopathy is a rare, autosomal recessive, inborn error of sialic acid metabolism, caused by mutations in GNE, the gene encoding UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase. The disease manifests as an adult-onset myopathy characterized by progressive skeletal muscle weakness and atrophy. There is no medical therapy available for this debilitating disease. Hyposialylation of muscle glycoproteins likely contributes to the pathophysiology of this disease. N-acetyl-D-mannosamine (ManNAc), an uncharged monosaccharide and the first committed precursor in the sialic acid biosynthetic pathway, is a therapeutic candidate that prevents muscle weakness in the mouse model of GNE myopathy. We conducted a first-in-human, randomized, placebo-controlled, double-blind, single-ascending dose study to evaluate safety and pharmacokinetics of ManNAc in GNE myopathy subjects. Single doses of 3 and 6g of oral ManNAc were safe and well tolerated; 10g was associated with diarrhea likely due to unabsorbed ManNAc. Oral ManNAc was absorbed rapidly and exhibited a short half-life (~2.4h). Following administration of a single dose of ManNAc, there was a significant and sustained increase in plasma unconjugated free sialic acid (Neu5Ac) (Tmax of 8-11h). Neu5Ac levels remained above baseline 48h post-dose in subjects who received a dose of 6 or 10g. Given that Neu5Ac is known to have a short half-life, the prolonged elevation of Neu5Ac after a single dose of ManNAc suggests that intracellular biosynthesis of sialic acid was restored in subjects with GNE myopathy, including those homozygous for mutations in the kinase domain. Simulated plasma concentration-time profiles support a dosing regimen of 6g twice daily for future clinical trials.
Published: 2017
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35. Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS

Author: Marjan Huizing, Melanie M. Bryan, Robert B. Hufnagel, Nathanial J. Tolman, Vladislav V. Speransky, Bernadette R. Gochuico, May Christine V. Malicdan, Karen L. Simon, Brian P. Brooks, James C. Mullikin, and William A. Gahl
Subjects: Male, 0301 basic medicine, Ocular albinism, Pathology, medicine.medical_specialty, Biogenesis of lysosome-related organelles complex 1, Endocrinology, Diabetes and Metabolism, Nonsense mutation, Biology, Biochemistry, Article, 03 medical and health sciences, Endocrinology, Genetics, medicine, Humans, Exome, Child, Molecular Biology, Exome sequencing, Platelet storage pool deficiency, Dysbindin, Sequence Analysis, DNA, medicine.disease, Oculocutaneous albinism, eye diseases, 030104 developmental biology, Codon, Nonsense, Hermanski-Pudlak Syndrome, Dystrophin-Associated Proteins, Hermansky–Pudlak syndrome
Abstract: Purpose Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7. Results A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising. He also experienced delayed motor and language development as a very young child; head and chest trauma resulted in intracranial hemorrhage with subsequent right hemiparesis and lung scarring. There was no clinical evidence of immunodeficiency or colitis. Whole mount transmission electron microscopy revealed absent platelet delta granules; platelet aggregation testing was abnormal. Exome sequencing revealed a homozygous nonsense mutation in the Dystrobrevin binding protein 1 (DTNBP1) gene [ NM_032122.4 : c.307C > T; p.Gln103*], previously reported in a Portuguese adult. The gene encodes the dysbindin subunit of BLOC-1. Dysbindin protein expression was negligible in our patient's dermal fibroblasts, while his DTNBP1 mRNA level was similar to that of a normal control. Conclusions Comprehensive clinical evaluation of the first pediatric case reported with HPS-7 reveals oculocutaneous albinism and platelet storage pool deficiency; his phenotype is consistent with findings in other patients with BLOC-1 disorders. This patient's markedly reduced Dysbindin protein expression in HPS-7 resulted from a mechanism other than nonsense mediated decay.
Published: 2017
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36. Combined alpha-delta platelet storage pool deficiency is associated with mutations in GFI1B

Author: David R. Adams, Carlos Ferreira, Meral Gunay-Aygun, Shirley M. Abraham, Karen L. Simon, Thomas C. Markello, May Christine V. Malicdan, William A. Gahl, and Dong Chen
Subjects: Male, Platelet Storage Pool Deficiency, 0301 basic medicine, Adolescent, Sequence analysis, Endocrinology, Diabetes and Metabolism, Repressor, Alpha (ethology), Plasma protein binding, Biology, medicine.disease_cause, Biochemistry, Article, 03 medical and health sciences, Endocrinology, Proto-Oncogene Proteins, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, Molecular Biology, Gene, Zinc finger, Mutation, Platelet storage pool deficiency, Zinc Fingers, Sequence Analysis, DNA, medicine.disease, Pedigree, Repressor Proteins, 030104 developmental biology, Protein Binding
Abstract: Combined alpha-delta platelet storage pool deficiency is characterized by the absence or reduction in the number of both alpha granules and dense bodies. This disorder can have variable severity as well as a variable inheritance pattern. We describe two patients from unrelated families with combined alpha-delta storage pool deficiency due to mutations in GFI1B, a zinc finger protein known to act as a transcriptional repressor of various genes. We demonstrate that this disease is associated with either a heterozygous mutation (de novo or familial) abrogating the binding of the zinc fingers with the promoter of its target genes, or by hypomorphic biallelic mutations in GFI1B leading to autosomal recessive inheritance.
Published: 2017
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37. The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease

Author: Rachel B. Ramoni, John J. Mulvihill, David R. Adams, Patrick Allard, Euan A. Ashley, Jonathan A. Bernstein, William A. Gahl, Rizwan Hamid, Joseph Loscalzo, Alexa T. McCray, Vandana Shashi, Cynthia J. Tifft, Anastasia L. Wise, Christopher J. Adams, Mercedes E. Alejandro, Mashid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Alan H. Beggs, Hugo J. Bellen, David Bernick, Anna Bican, David P. Bick, Camille L. Birch, Braden E. Boone, Lauren C. Briere, Donna M. Brown, Catherine A. Brownstein, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Katherine R. Chao, Gary D. Clark, Joy D. Cogan, Cynthia M. Cooper, William J. Craigen, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, David D. Draper, Annika M. Dries, Rachel Eastwood, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Paul G. Fisher, Trevor S. Frisby, Kate Frost, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen A. Golas, David B. Goldstein, Mary 'Gracie' G. Gordon, Sarah E. Gould, Jean-Philippe F. Gourdine, Brett H. Graham, Catherine A. Groden, Andrea L. Gropman, Mary E. Hackbarth, Melissa Haendel, Neil A. Hanchard, Lori H. Handley, Isabel Hardee, Matthew R. Herzog, Ingrid A. Holm, Ellen M. Howerton, Brenda Iglesias, Howard J. Jacob, Mahim Jain, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Alanna E. Koehler, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Lea Latham, Yvonne L. Latour, C. Christopher Lau, Jozef Lazar, Brendan H. Lee, Hane Lee, Paul R. Lee, Shawn E. Levy, Denise J. Levy, Richard A. Lewis, Adam P. Liebendorder, Sharyn A. Lincoln, Carson R. Loomis, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Casey Martin, Paul Mazur, Alexandra J. McCarty, Allyn McConkie-Rosell, Thomas O. Metz, Matthew Might, Paolo M. Moretti, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Sarah Sadozai, Katherine E. Schaffer, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Edwin K. Silverman, Janet S. Sinsheimer, Ariane G. Soldatos, Rebecca C. Spillmann, Kimberly Splinter, Joan M. Stoler, Nicholas Stong, Kimberly A. Strong, Jennifer A. Sullivan, David A. Sweetser, Sara P. Thomas, Nathanial J. Tolman, Camilo Toro, Alyssa A. Tran, Zaheer M. Valivullah, Eric Vilain, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Michael F. Wangler, Mike Warburton, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Alec A. Weech, Monte Westerfield, Matthew T. Wheeler, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, and Patricia A. Zornio
Subjects: 0301 basic medicine, Knowledge management, Genotype, Genotyping Techniques, Best practice, Disease, 030105 genetics & heredity, Bioinformatics, 03 medical and health sciences, Rare Diseases, Diagnostic model, Common fund, Genetics, Humans, Metabolomics, Functional studies, Genetics (clinical), Information Dissemination, business.industry, Disease mechanisms, Sequence Analysis, DNA, United States, Research objectives, Data sharing, Phenotype, 030104 developmental biology, National Institutes of Health (U.S.), Commentary, business
Abstract: Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.
Published: 2017
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38. A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay

Author: Kelly Schoch, Linyan Meng, Szabolcs Szelinger, David R. Bearden, Asbjorg Stray-Pedersen, Oyvind L. Busk, Nicholas Stong, Eriskay Liston, Ronald D. Cohn, Fernando Scaglia, Jill A. Rosenfeld, Jennifer Tarpinian, Cara M. Skraban, Matthew A. Deardorff, Jeremy N. Friedman, Zeynep Coban Akdemir, Nicole Walley, Mohamad A. Mikati, Peter G. Kranz, Joan Jasien, Allyn McConkie-Rosell, Marie McDonald, Stephanie Burns Wechsler, Michael Freemark, Sujay Kansagra, Sharon Freedman, Deeksha Bali, Francisca Millan, Sherri Bale, Stanley F. Nelson, Hane Lee, Naghmeh Dorrani, David B. Goldstein, Rui Xiao, Yaping Yang, Jennifer E. Posey, Julian A. Martinez-Agosto, James R. Lupski, Michael F. Wangler, Vandana Shashi, Wayne W. Grody, Samuel P. Strom, Eric Vilain, Joshua Deignan, Fabiola Quintero-Rivera, Sibel Kantarci, Sureni Mullegama, Sung-Hae Kang, Mercedes E. Alejandro, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Gary D. Clark, William J. Craigen, Shweta U. Dhar, Lisa T. Emrick, Brett H. Graham, Neil A. Hanchard, Mahim Jain, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Azamian S. Mashid, Paolo M. Moretti, Sarah K. Nicholas, Jordan S. Orange, Lorraine Potocki, Daryl A. Scott, Alyssa A. Tran, Hugo J. Bellen, Shinya Yamamoto, Christine M. Eng, Donna M. Muzny, Patricia A. Ward, Andrea L. Gropman, Yong-hui Jiang, Loren D.M. Pena, Rebecca C. Spillmann, Jennifer A. Sullivan, Nicole M. Walley, Alan H. Beggs, Lauren C. Briere, Cynthia M. Cooper, Laurel A. Donnell-Fink, Elizabeth L. Krieg, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Chris A. Walsh, Cecilia Esteves, Ingrid A. Holm, Isaac S. Kohane, Paul Mazur, Alexa T. McCray, Matthew Might, Rachel B. Ramoni, Kimberly Splinter, David P. Bick, Camille L. Birch, Braden E. Boone, Donna M. Brown, Dan C. Dorset, Lori H. Handley, Howard J. Jacob, Angela L. Jones, Jozef Lazar, Shawn E. Levy, J. Scott Newberry, Molly C. Schroeder, Kimberly A. Strong, Elizabeth A. Worthey, Jyoti G. Dayal, David J. Eckstein, Sarah E. Gould, Ellen M. Howerton, Donna M. Krasnewich, Carson R. Loomis, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Anastasia L. Wise, Ariane G. Soldatos, Matthew Brush, Jean-Philippe F. Gourdine, Melissa Haendel, David M. Koeller, Jennifer E. Kyle, Thomas O. Metz, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Euan A. Ashley, Jonathan A. Bernstein, Annika M. Dries, Paul G. Fisher, Jennefer N. Kohler, Daryl M. Waggott, Matt T. Wheeler, Patricia A. Zornio, Patrick Allard, Hayk Barseghyan, Esteban C. Dell’Angelica, Katrina M. Dipple, Matthew R. Herzog, Stan F. Nelson, Christina G.S. Palmer, Jeanette C. Papp, Janet S. Sinsheimer, Christopher J. Adams, Elizabeth A. Burke, Katherine R. Chao, Mariska Davids, David D. Draper, Tyra Estwick, Trevor S. Frisby, Kate Frost, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen A. Golas, Mary 'Gracie' G. Gordon, Catherine A. Groden, Mary E. Hackbarth, Isabel Hardee, Jean M. Johnston, Alanna E. Koehler, Lea Latham, Yvonne L. Latour, C. Christopher Lau, Denise J. Levy, Adam P. Liebendorder, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Alexandra J. McCarty, Jennifer L. Murphy, Michele E. Nehrebecky, Donna Novacic, Barbara N. Pusey, Sarah Sadozai, Katherine E. Schaffer, Prashant Sharma, Sara P. Thomas, Nathanial J. Tolman, Camilo Toro, Zaheer M. Valivullah, Colleen E. Wahl, Mike Warburton, Alec A. Weech, Guoyun Yu, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, Paul R. Lee, John H. Postlethwait, Monte Westerfield, Anna Bican, Rizwan Hamid, John H. Newman, John A. Phillips, Amy K. Robertson, and Joy D. Cogan
Subjects: Male, 0301 basic medicine, Microcephaly, Mutation, Missense, Biology, Cataract, Germline, 03 medical and health sciences, Neurodevelopmental disorder, Cataracts, Report, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Amino Acid Sequence, Child, Alleles, Genetics (clinical), Cerebral atrophy, Brain, Genetic Variation, Infant, medicine.disease, Magnetic Resonance Imaging, Neoplasm Proteins, Pedigree, 3. Good health, Repressor Proteins, Phenotype, 030104 developmental biology, Child, Preschool, Failure to thrive, Female, medicine.symptom, Spasms, Infantile, Genome-Wide Association Study
Abstract: Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 ( NACC1 ) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 −14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1 .
Published: 2017
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39. Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation

Author: Jonathan J. Lyons, Andrea L. Gropman, Marc G. Ghany, Lynne A. Wolfe, Carmen C. Brewer, John M. Schreiber, Shilpa Lingala, Audrey Thurm, Camilo Toro, Carlos Ferreira, Cristan Farmer, Virginia Kimonis, Constantine A. Stratakis, Ellen Macnamara, Beth Solomon, Eva H. Baker, Christina Lam, Wadih M. Zein, Sergio D. Rosenzweig, Donna M. Krasnewich, Tanya J. Lehky, William A. Gahl, Lea Latham, and Mariska Davids
Subjects: Adult, Male, 0301 basic medicine, Joint hypermobility, Pathology, medicine.medical_specialty, Glycosylation, Adolescent, Developmental Disabilities, Rubella, Article, Young Adult, 03 medical and health sciences, Atrophy, Cone dystrophy, Albumins, medicine, Humans, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, Global developmental delay, Child, NGLY1, Genetics (clinical), Glycoproteins, business.industry, Cerebrospinal Fluid Proteins, Bone age, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Mutation, Female, business, Congenital disorder
Abstract: The cytosolic enzyme N-glycanase 1, encoded by NGLY1, catalyzes cleavage of the β-aspartyl glycosylamine bond of N-linked glycoproteins, releasing intact N-glycans from proteins bound for degradation. In this study, we describe the clinical spectrum of NGLY1 deficiency (NGLY1-CDDG). Prospective natural history protocol. In 12 individuals ages 2 to 21 years with confirmed, biallelic, pathogenic NGLY1 mutations, we identified previously unreported clinical features, including optic atrophy and retinal pigmentary changes/cone dystrophy, delayed bone age, joint hypermobility, and lower than predicted resting energy expenditure. Novel laboratory findings include low cerebral spinal fluid (CSF) total protein and albumin and unusually high antibody titers toward rubella and/or rubeola following vaccination. We also confirmed and further quantified previously reported findings noting that decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features. Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions. Genet Med 19 2, 160–168.
Published: 2017
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40. A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3

Author: Hsiao-Tuan Chao, Mariska Davids, Elizabeth Burke, John G. Pappas, Jill A. Rosenfeld, Alexandra J. McCarty, Taylor Davis, Lynne Wolfe, Camilo Toro, Cynthia Tifft, Fan Xia, Nicholas Stong, Travis K. Johnson, Coral G. Warr, Shinya Yamamoto, David R. Adams, Thomas C. Markello, William A. Gahl, Hugo J. Bellen, Michael F. Wangler, May Christine V. Malicdan, Christopher J. Adams, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Alan H. Beggs, Jonathan A. Bernstein, David P. Bick, Camille L. Birch, Braden E. Boone, Lauren C. Briere, Donna M. Brown, Matthew Brush, Lindsay C. Burrage, Katherine R. Chao, Gary D. Clark, Joy D. Cogan, Cynthia M. Cooper, William J. Craigen, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Dan C. Dorset, David D. Draper, Annika M. Dries, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Paul G. Fisher, Trevor S. Frisby, Kate Frost, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen A. Golas, David B. Goldstein, Mary 'Gracie' G. Gordon, Sarah E. Gould, Jean-Philippe F. Gourdine, Brett H. Graham, Catherine A. Groden, Andrea L. Gropman, Mary E. Hackbarth, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Isabel Hardee, Matthew R. Herzog, Ingrid A. Holm, Ellen M. Howerton, Howard J. Jacob, Mahim Jain, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Alanna E. Koehler, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Lea Latham, Yvonne L. Latour, C. Christopher Lau, Jozef Lazar, Brendan H. Lee, Hane Lee, Paul R. Lee, Shawn E. Levy, Denise J. Levy, Richard A. Lewis, Adam P. Liebendorder, Sharyn A. Lincoln, Carson R. Loomis, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Laura A. Mamounas, Teri A. Manolio, Azamian S. Mashid, Paul Mazur, Allyn McConkie-Rosell, Alexa T. McCray, Thomas O. Metz, Matthew Might, Paolo M. Moretti, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Rachel B. Ramoni, Lance H. Rodan, Sarah Sadozai, Katherine E. Schaffer, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Vandana Shashi, Edwin K. Silverman, Janet S. Sinsheimer, Ariane G. Soldatos, Rebecca C. Spillmann, Kimberly Splinter, Joan M. Stoler, Kimberly A. Strong, Jennifer A. Sullivan, David A. Sweetser, Sara P. Thomas, Cynthia J. Tift, Nathanial J. Tolman, Alyssa A. Tran, Zaheer M. Valivullah, Eric Vilain, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Mike Warburton, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Alec A. Weech, Monte Westerfield, Matt T. Wheeler, Anastasia L. Wise, Lynne A. Worthe, Elizabeth A. Worthey, Yaping Yang, Guoyun Yu, and Patricia A. Zornio
Subjects: Central Nervous System, Male, 0301 basic medicine, Ataxia, Developmental Disabilities, Biology, Speech Disorders, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Report, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genitalia, Global developmental delay, Child, Transcription factor, Genetics (clinical), Zinc finger, Infant, Newborn, Infant, Zinc Fingers, Syndrome, medicine.disease, Hypotonia, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Mutation, Muscle Hypotonia, Homeobox, Female, medicine.symptom, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.
Published: 2017
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41. Free sialic acid storage disorder: Progress and promise

Author: Marjan Huizing, Mary E. Hackbarth, David R. Adams, Melissa Wasserstein, Marc C. Patterson, Steven U. Walkley, William A. Gahl, Kostantin Dobrenis, Jessica Foglio, Bruno Gasnier, Mary Hackbarth, Monkol Lek, May C.V. Malicdan, Liisa E. Paavola, Richard Reimer, Raymond Y. Wang, and Roberto Zoncu
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Ataxia, Organic Anion Transporters, Disease, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Animals, Humans, Symporters, Cerebellar ataxia, Coarse facial features, business.industry, General Neuroscience, Sialic Acid Storage Disease, Genetic Therapy, medicine.disease, N-Acetylneuraminic Acid, Sialic acid, 030104 developmental biology, Salla disease, chemistry, Cerebellar atrophy, medicine.symptom, business, N-Acetylneuraminic acid, 030217 neurology & neurosurgery, Stem Cell Transplantation
Abstract: Lysosomal free sialic acid storage disorder (FSASD) is an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the lysosomal sialic acid membrane exporter SLC17A5 (sialin). SLC17A5 defects cause free sialic acid and some other acidic hexoses to accumulate in lysosomes, resulting in enlarged lysosomes in some cell types and 10–100-fold increased urinary excretion of free sialic acid. Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia. Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features. Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease. The pathobiology of FSASD remains poorly understood and FSASD is likely underdiagnosed. Known patients have experienced a diagnostic delay due to the rarity of the disorder, absence of routine urine sialic acid testing, and non-specific clinical symptoms, including developmental delay, ataxia and infantile hypomyelination. There is no approved therapy for FSASD. We initiated a multidisciplinary collaborative effort involving worldwide academic clinical and scientific FSASD experts, the National Institutes of Health (USA), and the FSASD patient advocacy group (Salla Treatment and Research [S.T.A.R.] Foundation) to overcome the scientific, clinical and financial challenges facing the development of new treatments for FSASD. We aim to collect data that incentivize industry to further develop, obtain approval for, and commercialize FSASD treatments. This review summarizes current aspects of FSASD diagnosis, prevalence, etiology, and disease models, as well as challenges on the path to therapeutic approaches for FSASD.
Published: 2021
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42. Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism

Author: Vladislav V. Speransky, Jay N. Lozier, Karen L. Simon, Bernadette R. Gochuico, Wadih M. Zein, Khanh Nghiem, Kevin J. O'Brien, Anne T. Neff, Andrew R. Cullinane, Brigitte Osorio, Lisa R. Young, May Christine V. Malicdan, James C. Mullikin, and William A. Gahl
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Pathology, Endocrinology, Diabetes and Metabolism, Hemophilia B, Biochemistry, Gastroenterology, Article, 03 medical and health sciences, Endocrinology, Internal medicine, Genetics, Humans, Medicine, Exome, Desmopressin, Molecular Biology, business.industry, Intracellular Signaling Peptides and Proteins, Interstitial lung disease, medicine.disease, Oculocutaneous albinism, Phenotype, 030104 developmental biology, Albinism, Oculocutaneous, Hermanski-Pudlak Syndrome, Hemostasis, Mutation, Etiology, Female, Fresh frozen plasma, Hermansky–Pudlak syndrome, business, medicine.drug
Abstract: Purpose Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism. Results The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions. Conclusions This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient with Hermansky-Pudlak syndrome subtype 6.
Published: 2016
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43. First report of inherited thyroxine-binding globulin deficiency in Iran caused by a known de novo mutation in SERPINA7

Author: Fatemeh Jesmi, Fahimeh Soheilipour, William A. Gahl, Babak Behnam, Hassan Fazilaty, National Institutes of Health (US), and National Human Genome Research Institute (US)
Subjects: Signal peptide, medicine.medical_specialty, Globulin, Arginine, 030209 endocrinology & metabolism, Case Report, Iran, medicine.disease_cause, 03 medical and health sciences, Exon, 0302 clinical medicine, Endocrinology, TBG, Internal medicine, Genetics, medicine, Molecular Biology, Gene, lcsh:QH301-705.5, chemistry.chemical_classification, Mutation, lcsh:R5-920, biology, SERPINA7, Amino acid, chemistry, lcsh:Biology (General), 030220 oncology & carcinogenesis, biology.protein, Isoleucine, lcsh:Medicine (General)
Abstract: [Background] Thyroxine-binding globulin (TBG) is the main transporter of thyroid hormones in human serum, encoded by the gene TBG (SERPINA7), located in long arm of X-chromosome (Xq21-q22). Deficiency of SERPINA7 (serum protease inhibitor, clade A [alpha-1 antiproteinase, antitrypsin], member 7) leads to inherited TBG deficiency. Several mutations have been reported in the coding and noncoding regions of SERPINA7 in association with TGB deficiency., [Methods] Automated chemiluminescence immunoassays were used to determine TSH, free and total T4 and T3 (fT4, TT4, TT3) and TBG. Direct DNA sequencing identified the mutation in SERPINA7., [Results] We present a 3 and 4/12 year old boy, born premature, who was mismanaged as hypothyroidism before referral to our center, and was diagnosed with TBG deficiency at our center with a hemizygous substitution in exon 1, position c.347T > A, leading to replacement of isoleucine for arginine in position 96 (considering the first 20 amino acid signal peptide)., [Conclusion] This known mutation, reported as the first SERPINA7 mutation in Iran, emphasizes the point that endocrinologists should pay more attention to inherited TBG to prevent unnecessary treatment., This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA (Common Fund).
Published: 2016
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44. A Clinical Service to Support the Return of Secondary Genomic Findings in Human Research

Author: Steven M. Holland, Richard O. Cannon, Forbes D. Porter, Wendy S. Rubinstein, David A. Bluemke, Mark H. Greene, Sara Chandros Hull, William A. Gahl, Christine Grady, Leslie G. Biesecker, David B. Resnik, Andrew J. Darnell, David Goldman, Kenneth H. Fischbeck, and Howard Austin
Subjects: 0301 basic medicine, Service (systems architecture), Knowledge management, Computer science, MEDLINE, Genomics, Disease, 030105 genetics & heredity, Bioinformatics, 03 medical and health sciences, Intervention (counseling), Genetics, Humans, Genetic Predisposition to Disease, Genetics(clinical), Genetics (clinical), Exome sequencing, Incidental Findings, Scope (project management), Genome, Human, business.industry, 030104 developmental biology, Commentary, Human research, business, Sequence Analysis
Abstract: Human genome and exome sequencing are powerful research tools that can generate secondary findings beyond the scope of the research. Most secondary genomic findings are of low importance, but some (for a current estimate of 1%–3% of individuals) confer high risk of a serious disease that could be mitigated by timely medical intervention. The impact and scope of secondary findings in genome and exome sequencing will only increase in the future. There is considerable agreement that high-impact findings should be returned to participants, but many researchers performing genomic research studies do not have the background, skills, or resources to identify, verify, interpret, and return such variants. Here, we introduce a proposal for the formation of a secondary-genomic-findings service (SGFS) that would support researchers by enabling the return of clinically actionable sequencing results to research participants in a standardized manner. We describe a proposed structure for such a centralized service and evaluate the advantages and challenges of the approach. We suggest that such a service would be of greater benefit to all parties involved than present practice, which is highly variable. We encourage research centers to consider the adoption of a centralized SGFS.
Published: 2016
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45. Association of BRAF V600E with Hypothalamic-Pituitary-Adrenal Axis Involvement in Erdheim-Chester Disease

Author: Juvianee Estrada-Veras, Georgios Z. Papadakis, Louisa C. Boyd, William A. Gahl, Fady Hannah-Shmouni, Kevin O'Brien, and Amit Tirosh
Subjects: Inflammation, Erdheim-Chester Disease, medicine.medical_specialty, lcsh:RC648-665, Cortisol awakening response, medicine.drug_class, Adrenal gland, business.industry, Adrenal crisis, medicine.disease, lcsh:Diseases of the endocrine glands. Clinical endocrinology, BRAF, Histiocytosis, medicine.anatomical_structure, Endocrinology, Mineralocorticoid, Internal medicine, Erdheim–Chester disease, medicine, medicine.symptom, business, Hypothalamic–pituitary–adrenal axis, Glucocorticoid, Adrenal Insufficiency, medicine.drug
Abstract: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by uncontrolled inflammation resulting in fibro-inflammatory damage of multiple organs, including the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoid insufficiency may occur and is associated with an increased burden of disease and an increased risk of adrenal crisis. Sixty-one ECD subjects (46 males, age 54.3 ± 10.8 years) were evaluated; 56.1% (32/57) harbored a somatic activating BRAF V600E variant. Adrenal gland and sellar or suprasellar involvement was present in 18/57 (31.6%) and 9/57 (15.8%) subjects on computed tomography or magnetic resonance imaging, respectively. The BRAF-positive group was more likely to have adrenal gland involvement (56.2% vs. 20.0%; odds ratio (OR) 5.8, 95% confidence interval (CI) 1.5-17.1, P=0.008), with comparable rates for sellar or suprasellar involvement (28.1% vs. 20.0%; OR 1.6, 95% CI 0.5-5.4, P=0.5) and low random morning cortisol values (37.5% vs. 32.0%; OR 1.3, 95% CI 0.4-3.8, P=0.7). High-sensitivity C-reactive protein was significantly higher in the BRAF V600E-positive group with adrenal involvement when compared to the BRAF V600E-negative group without adrenal involvement (mean concentration: 40 mg/dL vs. 5 mg/dL, P=0.046). HPA axis in ECD tends to involve the adrenal glands in BRAF V600E-positive individuals, without influencing the rates of low cortisol levels, although there is a poor biochemical-radiological concordance in ECD. In this cohort, most subjects with HPA axis involvement did not require glucocorticoid or mineralocorticoid therapy. This study systematically demonstrates an association between the somatic activating BRAF V600E variant and the presence of radiographic and biochemical HPA axis involvement in ECD subjects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01417520
Published: 2020
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46. Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors

Author: Thomas C. Markello, Stephen G. Kahler, Noelle R. Danylchuk, Gretchen Golas, Irina Maric, Lynne A. Wolfe, Adolfo Garnica, Maya Lodish, Wadih M. Zein, David R. Adams, Constantine A. Stratakis, Eva H. Baker, G. Bradley Schaefer, May Christine V. Malicdan, Sergio D. Rosenzweig, William A. Gahl, Andrea L. Gropman, Christina Lam, Megan S. Kane, Carlos Ferreira, Cornelius F. Boerkoel, Donna M. Krasnewich, Marjan Huizing, and Mariska Davids
Subjects: Heterozygote, Glycosylphosphatidylinositols, Intellectual and Developmental Disabilities (IDD), Developmental Disabilities, Endocrinology, Diabetes and Metabolism, Clinical Sciences, Mutation, Missense, Glycosylphosphatidylinositol anchor, Biology, Compound heterozygosity, Biochemistry, Article, Frameshift mutation, Congenital, Endocrinology, Clinical Research, Genetics, medicine, 2.1 Biological and endogenous factors, Humans, Missense mutation, Exome, Flow cytometry, Global developmental delay, Aetiology, Child, Frameshift Mutation, Molecular Biology, Exome sequencing, Skin, Pediatric, Genetics & Heredity, Congenital disorder of glycosylation, Fibroblasts, medicine.disease, Hypotonia, Brain Disorders, Phenotype, Mutation, Congenital Structural Anomalies, Muscle Hypotonia, Missense, PIGT-CDG, medicine.symptom, Acyltransferases
Abstract: PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C>T encoding a previously described missense variant. Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders.
Published: 2015
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47. CTNS molecular genetics profile in a Persian nephropathic cystinosis population

Author: Babak Behnam, William A. Gahl, Mansoureh Akouchekian, Rozita Hosseini, Farideh Ghazi, H Otukesh, Zohreh Ataei Kachoei, and Shahram Teimourian
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Adolescent, Population, Cystinosis, Gene mutation, Biology, Iran, medicine.disease_cause, lcsh:RC870-923, CTNS, 03 medical and health sciences, Exon, Nephropathic Cystinosis, Molecular genetics, medicine, Humans, education, Child, Novel, Genetics, Mutation, education.field_of_study, Splice site mutation, Infant, medicine.disease, lcsh:Diseases of the genitourinary system. Urology, 030104 developmental biology, Amino Acid Transport Systems, Neutral, Nephrology, Child, Preschool, Female
Abstract: Purpose In this report, we document the CTNS gene mutations of 28 Iranian patients with nephropathic cystinosis age 1–17 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. Methods Cystinosis was primarily diagnosed by a pediatric nephrologist and then referred to the Iran University of Medical Sciences genetics clinic for consultation and molecular analysis, which involved polymerase chain reaction (PCR) amplification to determine the presence or absence of the 57-kb founder deletion in CTNS , followed by direct sequencing of the coding exons of CTNS . Results The common 57-kb deletion was not observed in any of the 28 Iranian patients. In 14 of 28 patients (50%), mutations were observed in exons 6 and 7. No mutation was detected in exon 5, and only one (3.6%) patient with cystinosis showed a previously reported 4-bp deletion in exon 3 of CTNS . Four patients (14.3%) had a previously reported mutation (c.969C>A; p.N323K) in exon 11, and five (18%) had novel homozygous deletions in exon 6 leading to premature truncation of the protein. These deletions included c.323delA; p.Q108RfsX10 in three individuals and c.257-258delCT; p.S86FfsX37 in two cases. Other frame-shift mutations were all novel homozygous single base pair deletion/insertions including one in CTNS exon 9 (c.661insT; p.V221CfsX6), and four (14.3%) in exon 4, i.e., c.92insG; p.V31GfsX28 in two and c.120delC; p.T40TfsX10 in two. In total, we identified eight previously reported mutations and eight novel mutations in our patients. The only detected splice site mutation (IVS3-2A>C) was associated with the insertion mutation in the exon 9. Conclusion This study, the first molecular genetic analysis of non-ethnic-specific Iranian nephropathic cystinosis patients, may provide guidance for molecular diagnostics of cystinosis in Iran.
Published: 2017
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48. Atypical presentation of GNE myopathy with asymmetric hand weakness

Author: John C. McKew, Nuria Carrillo-Carrasco, Kayla Williams, William A. Gahl, May Christine V. Malicdan, John Karl L. de Dios, Carla Ciccone, Galen O. Joe, Marjan Huizing, Jeffrey C. McClean, David A. Bluemke, Ami Mankodi, Robert Evers, and Joseph A. Shrader
Subjects: Adult, Male, Cumulative Trauma Disorders, Article, Grip strength, Atrophy, Muscular Diseases, Forearm, Multienzyme Complexes, medicine, Humans, Muscle, Skeletal, Myopathy, Genetics (clinical), Muscle Weakness, medicine.diagnostic_test, business.industry, Muscle weakness, Magnetic resonance imaging, GNE MYOPATHY, Anatomy, Hand, medicine.disease, Magnetic Resonance Imaging, body regions, medicine.anatomical_structure, Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Presentation (obstetrics), medicine.symptom, business, Follow-Up Studies
Abstract: GNE myopathy is a rare autosomal recessive muscle disease caused by mutations in GNE, the gene encoding the rate-limiting enzyme in sialic acid biosynthesis. GNE myopathy usually manifests in early adulthood with distal myopathy that progresses slowly and symmetrically, first involving distal muscles of the lower extremities, followed by proximal muscles with relative sparing of the quadriceps. Upper extremities are typically affected later in the disease. We report a patient with GNE myopathy who presented with asymmetric hand weakness. He had considerably decreased left grip strength, atrophy of the left anterior forearm and fibro-fatty tissue replacement of left forearm flexor muscles on T1-weighted magnetic resonance imaging. The patient was an endoscopist and thus the asymmetric hand involvement may be associated with left hand overuse in daily repetitive pinching and gripping movements, highlighting the possible impact of environmental factors on the progression of genetic muscle conditions.
Published: 2014
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49. Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith–Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity

Author: Stephen F. Traynelis, Karin Fuentes Fajardo, Lynne A. Wolfe, Conisha Holloman, Barbara K. Burton, Richard W. Hanson, James P. Snyder, Cornelius F. Boerkoel, Todd Holyoak, Ann C.M. Smith, David R. Adams, Hongjie Yuan, Cynthia J. Tifft, Thierry Vilboux, Gretchen Golas, Yan Huang, Douglas S. Kerr, Murat Sincan, Katrina H. Arajs, Parvin Hakimi, George Grahame, Hugo Vega, William A. Gahl, Thomas C. Markello, and Gordon Wells
Subjects: Retinoic acid induced 1, Endocrinology, Diabetes and Metabolism, DNA Mutational Analysis, Molecular Sequence Data, Nonsense mutation, Mutation, Missense, Single-nucleotide polymorphism, Protein structure function, Polymorphism, Single Nucleotide, Receptors, N-Methyl-D-Aspartate, Biochemistry, Article, Endocrinology, Genetics, medicine, Humans, Amino Acid Sequence, Child, Molecular Biology, Genetic Association Studies, Exome sequencing, Base Sequence, biology, Intracellular Signaling Peptides and Proteins, Smith–Magenis syndrome, medicine.disease, 3. Good health, HEK293 Cells, Child, Preschool, Mutation (genetic algorithm), Trans-Activators, biology.protein, Female, Phosphoenolpyruvate Carboxykinase (GTP), GRIN2B, Smith-Magenis Syndrome, Phosphoenolpyruvate Carboxykinase (ATP), Transcription Factors
Abstract: The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith–Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B , which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1 , which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.
Published: 2014
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50. The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience

Author: Cornelius F. Boerkoel, Catherine Groden, Lauren Lawrence, William A. Gahl, Camilo Toro, Dennis M.D. Landis, Michele Nehrebecky, Grace Park, Colleen E. Wahl, Cynthia J. Tifft, Murat Sincan, David R. Adams, Thomas C. Markello, Rena A. Godfrey, Fred Gill, Gretchen Golas, Ariane Soldatos, and Lynne A. Wolfe
Subjects: Adult, Male, Adolescent, Genetic counseling, Genetic Counseling, Article, Cohort Studies, Young Adult, incidental findings, Genetic variation, Humans, Medicine, Exome, Genetic Predisposition to Disease, Young adult, Child, Genetics (clinical), Exome sequencing, Family Health, Family health, Genetics, Genome, Human, business.industry, Genetic Diseases, Inborn, Genetic Variation, familial, Sequence Analysis, DNA, Middle Aged, NIH Undiagnosed Diseases Program, United States, National Institutes of Health (U.S.), Female, Human genome, secondary variants, business, exome sequencing, Metabolism, Inborn Errors, Cohort study
Abstract: Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants.Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data.We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable.Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family.
Published: 2014
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